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Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-20 , DOI: 10.1021/acs.jmedchem.9b01624 Yahu A Liu 1 , Qihui Jin 1 , Yefen Zou 1 , Qiang Ding 1 , Shanshan Yan 1 , Zhicheng Wang 1 , Xueshi Hao 1 , Bao Nguyen 1 , Xiaoyue Zhang 1 , Jianfeng Pan 1 , Tingting Mo 1 , Kate Jacobsen 1 , Thanh Lam 1 , Tom Y-H Wu 1 , H Michael Petrassi 1 , Badry Bursulaya 1 , Michael DiDonato 1 , W Perry Gordon 1 , Bo Liu 1 , Janine Baaten 1 , Robert Hill 1 , Vân Nguyen-Tran 1 , Minhua Qiu 1 , You-Qing Zhang 1 , Anwesh Kamireddy 1 , Sheryll Espinola 1 , Lisa Deaton 1 , Sukwon Ha 1 , George Harb 1 , Yong Jia 1 , Jing Li 1 , Weijun Shen 1 , Andrew M Schumacher 1 , Karyn Colman 1 , Richard Glynne 1 , Shifeng Pan 1 , Peter McNamara 1 , Bryan Laffitte 1 , Shelly Meeusen 1 , Valentina Molteni 1 , Jon Loren 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-20 , DOI: 10.1021/acs.jmedchem.9b01624 Yahu A Liu 1 , Qihui Jin 1 , Yefen Zou 1 , Qiang Ding 1 , Shanshan Yan 1 , Zhicheng Wang 1 , Xueshi Hao 1 , Bao Nguyen 1 , Xiaoyue Zhang 1 , Jianfeng Pan 1 , Tingting Mo 1 , Kate Jacobsen 1 , Thanh Lam 1 , Tom Y-H Wu 1 , H Michael Petrassi 1 , Badry Bursulaya 1 , Michael DiDonato 1 , W Perry Gordon 1 , Bo Liu 1 , Janine Baaten 1 , Robert Hill 1 , Vân Nguyen-Tran 1 , Minhua Qiu 1 , You-Qing Zhang 1 , Anwesh Kamireddy 1 , Sheryll Espinola 1 , Lisa Deaton 1 , Sukwon Ha 1 , George Harb 1 , Yong Jia 1 , Jing Li 1 , Weijun Shen 1 , Andrew M Schumacher 1 , Karyn Colman 1 , Richard Glynne 1 , Shifeng Pan 1 , Peter McNamara 1 , Bryan Laffitte 1 , Shelly Meeusen 1 , Valentina Molteni 1 , Jon Loren 1
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Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human β-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).
中文翻译：
用于治疗 1 型糖尿病的选择性 DYRK1A 抑制剂：6-氮杂吲哚衍生物 GNF2133 的发现。
自身免疫缺陷以及 β 细胞质量或功能的破坏可能导致胰岛素水平不足，从而导致高血糖和糖尿病。因此，促进β细胞增殖可能是糖尿病干预的一种方法。在本报告中，我们描述了一种有效且选择性的 DYRK1A 抑制剂 GNF2133 的发现，该抑制剂是通过优化 6-氮杂吲哚筛选命中而确定的。在体外，GNF2133 能够增殖啮齿动物和人类 β 细胞。在体内，GNF2133 在大鼠胰岛素促进剂和白喉毒素 A (RIP-DTA) 小鼠中表现出显着的剂量依赖性葡萄糖处理能力和胰岛素分泌能力，以响应葡萄糖强化精氨酸诱导的胰岛素分泌 (GPAIS) 挑战。本文描述的工作为 1 型糖尿病 (T1D) 的疾病改变治疗干预措施提供了新途径。
更新日期：2020-02-20
中文翻译：
用于治疗 1 型糖尿病的选择性 DYRK1A 抑制剂：6-氮杂吲哚衍生物 GNF2133 的发现。
自身免疫缺陷以及 β 细胞质量或功能的破坏可能导致胰岛素水平不足，从而导致高血糖和糖尿病。因此，促进β细胞增殖可能是糖尿病干预的一种方法。在本报告中，我们描述了一种有效且选择性的 DYRK1A 抑制剂 GNF2133 的发现，该抑制剂是通过优化 6-氮杂吲哚筛选命中而确定的。在体外，GNF2133 能够增殖啮齿动物和人类 β 细胞。在体内，GNF2133 在大鼠胰岛素促进剂和白喉毒素 A (RIP-DTA) 小鼠中表现出显着的剂量依赖性葡萄糖处理能力和胰岛素分泌能力，以响应葡萄糖强化精氨酸诱导的胰岛素分泌 (GPAIS) 挑战。本文描述的工作为 1 型糖尿病 (T1D) 的疾病改变治疗干预措施提供了新途径。
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